Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aß42) aggregates leads to sub-stoichiometric inhibition of amyloid formation.

The human molecular chaperone protein DNAJB6 was recently found to inhibit the formation of amyloid fibrils from polyglutamine peptides associated with neurodegenerative disorders such as Huntington disease. We show in the present study that DNAJB6 also inhibits amyloid formation by an even more aggregation-prone peptide (the amyloid-beta peptide, Aß42, implicated in Alzheimer disease) in a highly efficient manner. By monitoring fibril formation using Thioflavin T fluorescence and far-UV CD spectroscopy, we have found that the aggregation of Aß42 is retarded by DNAJB6 in a concentration-dependent manner, extending to very low sub-stoichiometric molar ratios of chaperone to peptide. Quantitative kinetic analysis and immunochemistry studies suggest that the high inhibitory efficiency is due to the interactions of the chaperone with aggregated forms of Aß42 rather than the monomeric form of the peptide. This interaction prevents the growth of such species to longer fibrils and inhibits the formation of new amyloid fibrils through both primary and secondary nucleation. A low dissociation rate of DNAJB6 from Aß42 aggregates leads to its incorporation into growing fibrils and hence to its gradual depletion from solution with time. When DNAJB6 is eventually depleted, fibril proliferation takes place, but the inhibitory activity can be prolonged by introducing DNAJB6 at regular intervals during the aggregation reaction. These results reveal the highly efficacious mode of action of this molecular chaperone against protein aggregation, and demonstrate that the role of molecular chaperones can involve interactions with multiple aggregated species leading to the inhibition of both principal nucleation pathways through which aggregates are able to form.

Protective and therapeutic effects of Argyreia speciosa against ethanol-induced gastric ulcer in rats.

The protective and therapeutic effects of Argyreia speciosa Sweet (Convolvulaceae) against ethanol-induced gastric ulcer in rats were evaluated. Ethanolic and water extracts of the aerial plant parts (200 mg/kg body weight) were orally administered daily for seven days prior to or after ulceration with one oral dose of 1 mL absolute ethanol on 24-h empty stomachs. Rats were divided into eleven groups. Group 1 served as control. To groups 2 and 3 each extract was administered. Groups 4 to 6 received each extract or ranitidine (100 mg/kg body weight) prior to ulcer induction. Groups 7 to 9 received each extract or ranitidine post ulcer induction. Groups 10 and 11 were gastric ulcerative rats after one hour and one week of ethanol induction. The evaluation was done through measuring ulcer indices: stomach acidity and volume, lesion counts, mucus, and prostaglandin E2 contents. Oxidative stress marker, i. e. malondialdehyde, glutathione, and superoxide dismutase, were estimated. Certain marker enzymes for different cell organelles, i. e. succinate and lactate dehydrogenases, glucose-6-phosphatase, acid phosphatase, and 5'-nucleotidase, were evaluated. The work was extended to determine the collagen content and the histopathological assessment of the stomach. Gastric ulcer exhibited a significant elevation of the ulcer index, antioxidant levels, collagen content, and the marker enzymes. The water extract attenuated these increments and was more potent as a protective agent, while the ethanol extract exhibited stronger therapeutic potency. In conclusion, A. speciosa acted as antiulcer agent. More detailed studies are required to identify the compounds responsible for the pharmacological effect.

Association of lipoprotein lipase and apolipoprotein C-III genes polymorphism with acute myocardial infarction in diabetic patients.

Lipoprotein lipase (LPL) and Apolipoprotein C-III (APOC-III) play an important role in lipid metabolism. The aim of this study was to explore the possible associations of the gene polymorphisms (LPL HindIII, LPL Ser(447)-Ter and APOC3 SstI), diabetes mellitus, and plasma lipids with myocardial infarction. The polymorphisms were assessed by restriction assay in 200 Egyptian MI patients (100 diabetic and 100 non-diabetic) and 100 healthy controls. This study demonstrated that individuals with the H2H2 genotype or S2 allele have more than three times higher relative risk of suffering from MI than those carrying the H1H1 or S1S1. Type 2 DM mainly lowers HDL-C levels in MI patients who carry H2H2 or S2S2 genotype and increases TC, TG, and LDL levels in MI patients carrying H2H2 or S2S2 genotype compared with non-diabetic MI patients carrying the same genotypes. In S447X polymorphism, it was observed that DM led to loss of the protective lipid profile in MI patients carrying 447XX genotype. These findings suggest that H2H2 or S2S2 genotypes are associated with dyslipidemia and increased risk of myocardial infarction. The S447X polymorphism is associated with a favorable lipid profile. However, the association of diabetes mellitus with these polymorphisms leads to unfavorable lipid profile.

Zingiber officinale extract and omega-3 fatty acids ameliorate endoplasmic reticulum stress in a nonalcoholic fatty liver rat model.

Endoplasmic reticulum (ER) stress was reported to play a major role in non-alcoholic fatty liver disease (NAFLD) induction and progression. Here, we study the effect of Zingiber officinale and omega-3 fatty acids on ER stress for treating NAFLD. Male Wistar rats were fed on a normal diet (control group) or high-fat diet (HFD) for 8 weeks. The HFD rats were later treated with vehicle, omega-3 or with Z. officinale extract. HFD group demonstrated significantly more body weight gain and higher plasma lipid profile, glucose, and hepatic enzymes. The expressions of lipogenic ChREBP and ER stress genes CHOP, XBP1, and GRP78 were increased. This was accompanied by intrahepatic fat accumulation visualized by hepatic morphology and H&E-stained sections. Treatment with Z. officinale and omega-3 fatty acids reverted these changes into a normal healthy state. From these results, we prove that both therapeutic approaches can be potential drugs for treating NAFLD besides other ER stress-associated diseases. PRACTICAL APPLICATIONS: The effect of Zingiber officinale extract and omega-3 fatty acid on ER stress associated with NAFLD was investigated. The results revealed that Z. officinale extract and omega-3 fatty acids significantly inhibited ER stress and intrahepatic fat accumulation with the upper hand for Z. officinale extract. Both can be used as future promising therapies for the treatment of NAFLD patients and also treating different diseases that involve ER stress as a pathological modulator like diabetes mellitus, Alzheimer's disease, Parkinson's disease, and cancer.

Turmeric-based diet can delay apoptosis without modulating NF-kappaB in unilateral ureteral obstruction in rats.

The unilateral ureteral obstruction (UUO) model of renal injury in rat is characterized by nuclear factor kappaB (NF-kappaB) activation and tumour necrosis factor alpha (TNF-alpha) production, which induces apoptosis via activation of caspase 8 resulting in cell death. Curcumin, the major component found in turmeric spice, has been reported to provide protection against fibrosis and apoptosis elicited by UUO. This study examined the effects of a turmeric-based diet (5% w/w) on the apoptotic pathway induced by UUO in rats after 30 days of ligation. Administration of a turmeric-based diet demonstrated a significant decrease (P<0.05) in mRNA expression of TNF-alpha and caspase 8, but not NF-kappaB, expression, which may contribute to the protective role of the turmeric-based diet. We conclude that a turmeric-based diet can delay apoptosis without modulating NF-kappaB, so as not to sensitize the mesangial cells to the apoptotic stimuli.

Frequent inadequate supply of micronutrients in fast food induces oxidative stress and inflammation in testicular tissues of weanling rats.

Fast food is high in energy density and low in essential micronutrient density, especially zinc (Zn), of which antioxidant processes are dependent. We have tested the hypothesis that frequent fast food consumption could induce oxidative damage associated with inflammation in weanling male rats in relevance to Zn deprivation, which could adversely affect testis function. Zn and iron (in plasma and testicular tissue), plasma antioxidant vitamins (A, E, and C), as well as testicular superoxide dismutase (SOD) and reduced glutathione (GSH), lipid peroxidation indexes (thiobarbituric acid reactive substances (TBARS) and lipoprotein oxidation susceptibility (LOS)), and inflammatory markers (plasma C-reactive protein (CRP) and testicular tumour necrosis factor-alpha (TNF-alpha)) were determined. Serum testosterone and histological examination of the testis were performed also. We found a severe decrease in antioxidant vitamins and Zn, with concomitant iron accumulation. Zinc deficiency correlated positively with SOD, GSH, antioxidant vitamins and testosterone, and negatively with TBARS, LOS, CRP and TNF-alpha, demonstrating a state of oxidative stress and inflammation. We concluded that micronutrient deficiency, especially Zn, enhanced oxidative stress and inflammation in testicular tissue leading to underdevelopment of testis and decreased testosterone levels.

Effect of 6-gingerol on AMPK- NF-κB axis in high fat diet fed rats.

OBJECTIVES: Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a central role in metabolic homeostasis and regulation of inflammatory responses through attenuation of nuclear factor kappa-B (NF-κB), Thus AMPK may be a promising pharmacologic target for the treatment of various chronic inflammatory diseases. We examined the effect of 6-gingerol, an active ingredient of ginger on AMPK-NF-κB pathway in high fat diet (HFD) rats in comparison to fish oil. METHODS: Protein levels of AMPK-α1 and phosphorylated AMPK-α1 were measured by western blot while Sirtuin 6 (Sirt-6), resistin and P65 were estimated by RT-PCR, TNF-α was determined by ELISA, FFAs were estimated chemically as well as the enzymatic determination of the metabolic parameters. RESULTS: 6-Gingerol substantially enhanced phosphorylated AMPK-α1 more than fish oil and reduced the P65 via upregulation of Sirt-6 and downregulation of resistin, and resulted in attenuation of the inflammatory molecules P65, FFAs and TNF-α more than fish oil treated groups but in an insignificant statistical manner, those effects were accompanied by a substantial hypoglycemic effect. CONCLUSION: Gingerol treatment effectively modulated the state of inflammatory privilege in HFD group and the metabolic disorders via targeting the AMPK-NF-κB pathway, through an increment in the SIRT-6 and substantial decrement in resistin levels.

Effect of curcumin on TNFR2 and TRAF2 in unilateral ureteral obstruction in rats.

OBJECTIVES: Tumor necrosis factor α (TNF-α) is implicated in the pathophysiology of renal obstruction through its interactions with two TNF-α receptors: TNFR1 and TNFR2. Activation of TNFR1 leads to the recruitment of the adaptor TNFR-associated death domain protein (TRADD), which binds the Ser/Thr kinase receptor-interacting protein (RIP) and TNFR-associated factors 2 (TRAF2). This TRADD-RIP-TRAF complex causes activation of the antiapoptotic pathway and inhibits caspase 8 activation. Meanwhile, activation of TNFR2 leads to depletion of TRAF2 and enhancement of the apoptotic pathway. Curcumin, the major component found in turmeric spice, has been reported to possess a protective role against renal injury elicited by unilateral ureteral obstruction (UUO). The present study aimed mainly to address the cytoprotective role of curcumin-rich diet (5% w/w) on the apoptotic pathway induced by UUO in rats after 30 d of ligation. METHODS: The levels of mRNA for TNFR1, TNFR2, RIP, TRAF2, and caspase 8 were measured by reverse transcription-polymerase chain reaction. The levels of TNF-α was determined by ELISA. Kidney sections were exposed to histologic and morphometric studies. RESULTS: Administration of curcumin decreased TNF-α, TNFR2, and caspase 8 without affecting TNFR1 levels. The gene expression levels of the antiapoptotic molecules RIP and TRAF2 were increased. CONCLUSIONS: The cytoprotective role of curcumin relies on its ability to decrease the TNFR2 mRNA and enhance the antiapoptotic molecules RIP and TRAF2 to decrease the apoptotic pathway via decreasing the caspase 8.

Effect of silibinin and vitamin E on the ASK1-p38 MAPK pathway in D-galactosamine/lipopolysaccharide induced hepatotoxicity.

Apoptosis signal-regulating kinase 1 (ASK1), a redox-sensor mitogen-activated protein kinase kinase kinase (MAPKKK) that activates p38 MAPK pathways in oxidative stress-induced hepatotoxicity in D-galactosamine/lipopolysaccharide (D-GalN/LPS) model, is a key central pathway in which specific targeting of ASK1 deactivation is of a great therapeutic potential. We tested the effect of silibinin and vitamin E in curative and prophylactic manner of treatment on the negative modulators of ASK1, thioredoxin1 (Trx1), thioredoxin reductase1 (TrxR1), and the protein phosphatase (PP5), whereas they have previously proven to have hepatoprotective effect. Either curative or prophylactic silibinin and vitamin E groups significantly decreased ASK1 and p38 MAPK levels through increasing the gene expression of Trx1, TrxR1, and PP5 to reduce the oxidative stress as demonstrated by decreasing the levels of NADPH oxidase 4 (NOX4), TBARS and conjugated diene with a concomitant increase in the levels of GSH, CAT, and SOD. These results were confirmed by histopathology examination which illustrated progressive degenerative changes of hepatocytes such as hydropic degeneration, vacuolation, pyknosis, karyolysis, and loss of architecture of some cells in D-GalN/LPS treatment, and these features were alleviated with silibinin and vitamin E administration. In conclusion, silibinin and vitamin E decreased ASK1-p38 MAPK pathway through deactivating the upstream signalling ASK1 molecule via increasing the levels of Trx1 and TrxR1 as well as the PP5 to alleviate in D-GalN/LPS induced hepatotoxicity.

Dietary fatty acid unsaturation levels, lipoprotein oxidation and circulating chemokine in experimentally induced atherosclerotic rats.

The dietary balance of long-chain fatty acids may influence processes involving leukocyte endothelial interactions, such as atherogenesis and inflammation. The relationship between proatherogenic lipoproteins and chemotactic motility is still controversial. However, the interaction of the former can increase recruitment of monocytes to the vessel walls and accelerate the events of atherogenesis. The current study examined the effects of unsaturated fatty acid levels on the oxidative susceptibility of lipoprotein, chemokine expressions and their relationship to atherosclerotic lesion development in experimental rats. Male Wistar rats were fed an atherogenic diet for 4 months and the diet was then supplemented with 10% v/w of virgin olive oil (OO group), sunflower oil (SO group) or fish oil (FO group) for 4 and 8 weeks. Blood samples were collected at four time points: at baseline, after feeding with the atherogenic diet and during the dietary regimen (4 and 8 weeks). Plasma lipid profile and lipoprotein oxidative susceptibility (LOS), C-reactive protein (CRP), monocyte chemoattractant protein (MCP-1), and regulated upon activation normal T-cell expressed and secreted (RANTES) were measured. The superoxide dismutase (SOD) and reduced glutathione (GSH) antioxidant activities were also studied in aortic segments. Histological assessment of the aortic segment was determined. Compared to baseline data, the high-fat and cholesterol-enriched diet increased atheroma formation, plasma LOS and inflammatory indexes (CRP, MCP-1, RANTES). However, it dramatically reduced aortic SOD and GSH contents. Dietary treatment of atherosclerotic rats with OO greatly reduced LOS and remarkably increased aortic SOD and GSH contents as compared to the SO- and FO-treated groups. The FO-supplemented diet had a more pronounced lowering effect on MCP-1 and RANTES compared to the OO and SO diets. In conclusion, this study demonstrated a strong relationship between LOS and circulating levels of chemokines. OO is a potent antioxidant and moderate anti-inflammatory, which effectively reduced aortic atherosclerotic lesions more than the SO- or FO-treated groups in male Wistar rats.

Evaluation of the amyloid beta-GFP fusion protein as a model of amyloid beta peptides-mediated aggregation: a study of DNAJB6 chaperone.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation and aggregation of extracellular amyloid ß (Aß) peptides and intracellular aggregation of hyper-phosphorylated tau protein. Recent evidence indicates that accumulation and aggregation of intracellular amyloid ß peptides may also play a role in disease pathogenesis. This would suggest that intracellular Heat Shock Proteins (HSP) that maintain cellular protein homeostasis might be candidates for disease amelioration. We recently found that DNAJB6, a member of DNAJ family of heat shock proteins, effectively prevented the aggregation of short aggregation-prone peptides containing large poly glutamines (associated with CAG repeat diseases) both in vitro and in cells. Moreover, recent in vitro data showed that DNAJB6 can delay the aggregation of Aß42 peptides. In this study, we investigated the ability of DNAJB6 to prevent the aggregation of extracellular and intracellular Aß peptides using transfection of human embryonic kidney 293 (HEK293) cells with Aß-green fluorescent protein (GFP) fusion construct and performing western blotting and immunofluorescence techniques. We found that DNAJB6 indeed suppresses Aß-GFP aggregation, but not seeded aggregation initiated by extracellular Aß peptides. Unexpectedly and unlike what we found for peptide-mediated aggregation, DNAJB6 required interaction with HSP70 to prevent the aggregation of the Aß-GFP fusion protein and its J-domain was crucial for its anti-aggregation effect. In addition, other DNAJ proteins as well as HSPA1a overexpression also suppressed Aß-GFP aggregation efficiently. Our findings suggest that Aß aggregation differs from poly glutamine (Poly Q) peptide induced aggregation in terms of chaperone handling and sheds doubt on the usage of Aß-GFP fusion construct for studying Aß peptide aggregation in cells.

Cerium oxide nanoparticles alleviate oxidative stress and decreases Nrf-2/HO-1 in D-GALN/LPS induced hepatotoxicity.

Translocation of the master regulator of antioxidant-response element-driven antioxidant gene, nuclear factor erythroid 2 (Nrf-2) from the cytoplasm into the nucleus and triggering the transcription of hemoxygenase-1 (HO-1) to counteract the oxidative stress is a key feature in D-galactoseamine and lipopolysaccharide (D-GALN/LPS) induced hepatotoxicity. We mainly aimed to study the effect of cerium oxide (CeO2) nanoparticles on Nrf-2/HO-1 pathway whereas; it has previously shown to have an antioxidant effect in liver models. Administration of CeO2 nanoparticles significantly decreased the translocation of the cytoplasmic Nrf-2 with a concomitant decrement in the gene expression of HO-1 as it reveals a powerful antioxidative effect as indicated by the significant increase in the levels of glutathione (GSH), glutathione peroxidase (GPX1), glutathione reductase (GR), superoxide dismutase (SOD) and catalase. In synchronization, a substantial decrement in the levels of inducible nitric oxide synthase (iNOS), TBARS and percentage of DNA fragmentation was established. These results were confirmed by histopathology examination which showed a severe degeneration, haemorrhages, widened sinusoids and focal leukocyte infiltration in D-GALN/LPS treatment and these features were alleviated with CeO2 administration. In conclusion, CeO2 is a potential antioxidant that can effectively decrease the translocation of the cytoplasmic Nrf-2 into the nucleus and decrease HO-1 in D-GALN/LPS induced hepatotoxicity.

Oxytocin inhibits NADPH oxidase and P38 MAPK in cisplatin-induced nephrotoxicity.

Oxidative stress significantly contributes to cisplatin (CP)-associated cytotoxicity, and use of antioxidants could counteract such cytotoxic effects of CP. The major biochemical pathway for reactive oxygen species (ROS) formation proceeds through O2⁻ production, which is generated by NADPH oxidase, such oxidative stress can activate p38 MAPK to intensify the cytotoxic effect of CP. We mainly aimed to study the protective effect of oxytocin (OT) on CP-induced nephrotoxicity whereas; it was previously shown to have anti-inflammatory effects in different inflammation models. Administration of OT significantly decreased the gene expression of both NADPH oxidase and P38 MAPK, nitric oxide (NO), myloperoxidase (MPO), and TBARS, furthermore it increased the renal tissue levels of antioxidants; reduced glutathione (GSH), and superoxide dismutase (SOD). Histologically, OT reduced the monocellular infiltration as well as the tubular damage in CP-induced nephrotoxicity. In conclusion OT has a powerful antioxidant effect that can alleviate the CP-induced nephrotoxicity through inhibition of NADPH oxidase and P38 MAPK resulting in improvement of kidney functions.

Zingiber officinale acts as a nutraceutical agent against liver fibrosis.

BACKGROUND/OBJECTIVE: Zingiber officinale Roscoe (ginger) (Zingiberaceae) has been cultivated for thousands of years both as a spice and for medicinal purposes. Ginger rhizomes successive extracts (petroleum ether, chloroform and ethanol) were examined against liver fibrosis induced by carbon tetrachloride in rats. RESULTS: The evaluation was done through measuring antioxidant parameters; glutathione (GSH), total superoxide dismutase (SOD) and malondialdehyde (MDA). Liver marker enzymes; succinate and lactate dehydrogenases (SDH and LDH), glucose-6-phosphatase (G-6-Pase), acid phosphatase (AP), 5'- nucleotidase (5'NT) and liver function enzymes; aspartate and alanine aminotransferases (AST and ALT) as well as cholestatic markers; alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin were estimated. Liver histopathological analysis and collagen content were also evaluated. Treatments with the selected extracts significantly increased GSH, SOD, SDH, LDH, G-6-Pase, AP and 5'NT. However, MDA, AST, ALT ALP, GGT and total bilirubin were significantly decreased. CONCLUSIONS: Extracts of ginger, particularly the ethanol one resulted in an attractive candidate for the treatment of liver fibrosis induced by CCl4. Further studies are required in order to identify the molecules responsible of the pharmacological activity.

Comparative study between the effect of the peroxisome proliferator activated receptor-alpha ligands fenofibrate and n-3 polyunsaturated fatty acids on activation of 5'-AMP-activated protein kinase-alpha1 in high-fat fed rats.

OBJECTIVES: Obesity is a risk factor for type 2 diabetes mellitus. It results from an energy imbalance in which energy intake exceeds energy expenditure. The cellular fuel gauge 5'-AMP-activated protein kinase (AMPK) is a heterotrimeric protein consisting of one catalytic subunit (alpha) and two non-catalytic subunits (beta and gamma), and approximately equal levels of alpha1 and alpha2 complexes are present in the liver. AMPK regulates metabolic pathways in response to metabolic stress and in particular ATP depletion to switch on energy-producing catabolic pathways such as beta-oxidation of fatty acids and switch off energy-depleting processes such as synthesis of fatty acid and cholesterol. A high-fat diet alters AMPK-alpha1 gene expression in the liver and skeletal muscle of rats and results in body weight gain and hyperglycaemia. The aim of this study was to investigate and compare the potential effects of peroxisome proliferator-activated receptor (PPAR)-alpha agonists fenofibrate and n-3 polyunsaturated fatty acids (PUFAs) in modulation of AMPK-alpha1 activity in liver and skeletal muscle of high-fat diet fed rats. METHODS: Reverse transcription-polymerase chain reaction was used for determination of AMPK-alpha1 in liver and soleus muscle and both PPAR-alpha and CPT-1 in hepatic tissues. Serum, total cholesterol, triacylglycerol, fatty acid and fasting blood glucose were determined colorimetrically. KEY FINDINGS: Both PPAR-alpha agonists, fenofibrate and n-3 PUFA, increased the mRNA expression of AMPK-alpha1 activity in liver and skeletal muscle of obese diabetic rats. Fenofibrate was superior in its activation of hepatic mRNA expression of AMPK-alpha 1 to exert more lipolytic effect and body weight reduction, as estimated through the decrease of triacylglycerol output and serum levels of fatty acid on the one hand and the increase in CPT-1 mRNA expression, the key enzyme in beta-oxidation of fatty acid, on the other hand. n-3 PUFA activated AMPK-alpha1 mRNA expression in skeletal muscle much more than fenofibrate to reveal more hypoglycaemic effect. CONCLUSIONS: The PPAR-alpha agonists fenofibrate and n-3 PUFA could efficiently activate AMPK-alpha1 mRNA expression in liver and skeletal muscle to exert body weight reduction and hypoglycaemic effect, respectively.

Interleukin-10 to tumor necrosis factor-alpha ratio is a predictive biomarker in nonalcoholic fatty liver disease: interleukin-10 to tumor necrosis factor-alpha ratio in steatohepatitis.

OBJECTIVES: Fatty liver disease is commonly associated with diabetes mellitus (DM). Insulin resistance (IR) as an investigative biomarker is only concerned with fatty liver that results from DM type 2 associated with metabolic syndrome. Irrespective of IR, DM is generally characterized by overproduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), whereas action of the latter is modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). The aim of this study was to investigate the efficacy of using TNF-alpha alone or IL-10/TNF-alpha ratio compared to IR, as a promising biomarker for fatty liver assessment in DM. Furthermore, we hypothesized that using garlic as an immunomodulator may decrease TNF-alpha and increase IL-10 production to improve steatohepatitis. METHODS: DM was induced metabolically by a high-fat diet to bring about IR, or chemically by alloxan, producing insulin deficiency, in male albino rats. Garlic powder was supplemented (15 mg/kg per day) for 3 weeks. Fatty liver was depicted histologically and biochemically (aspartic aminotransferase, alanine aminotransferase, HOMA-IR, TNF-alpha, IL-10, IL-10/TNF-alpha ratio). RESULTS: We found that, in contrast to obese rats, garlic decreased IL-10/TNF-alpha ratio, despite decreasing TNF-alpha in alloxan diabetic rats in agreement with the histology, which revealed more prominent improvement in the obese group. Moreover, the effect of garlic was not linked to improvement of IR in obese rats. CONCLUSION: We conclude that IL-10/TNF-alpha ratio may be considered as a convenient biomarker for investigation of fatty liver of different grades, apart from being associated with IR, and immunomodulation of this ratio in favor of increasing it may exert significant improvement.

Effect of age receptor blocker and/or anti-inflammatory coadministration in relation to glycation, oxidative stress and cytokine production in stz diabetic rats.

Until now the relation between advanced glycation end products (AGEs) and vascular lesion is still controversial. However, the interaction of the former with a receptor triggers the synthesis of cytokines particularly interleukin 1- beta(IL-1 beta) and tumour necrosis factor- alpha(TNFalpha ). Subsequent release of nitric oxide (NO) may in turn induce certain damage to beta cell islets. Several arguments indicated that AGEs and reactive oxygen intermediates (ROIs) could alter the function of the vessel wall. Therefore, this study was undertaken to investigate the effectiveness of aminoguanidine, AG (inhibitor of AGE formation) joined with omega -3-fatty acids, omega 3FAs (anti-inflammatory immunosuppressive drug) in STZ diabetic rats. Diabetes was induced in 48 female albino Wistar rats by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 50 mg kg (-1)). Diabetic animals were treated with AG (50 mg kg(-1) ) and/or omega 3FAs (12 mg kg (-1)) daily and orally for 4 weeks. Groups of age matched diabetic rats ( n= 10) and healthy animals ( n= 10) served as positive and negative controls. At the end of the study, plasma glucose, fructosamine, total cholesterol (TC), high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), the susceptibility of LDL to copper-catalysed oxidation, catalase activity, NO, IL-1 beta, TNF alpha were measured. Histopathological assessment of pancreatic slices were also determined. Diabetes remarkably increased plasma glucose, fructosamine and dyslipidaemia (increased TC, LDLC and decreased HDLC). Oxidative markers like oxidative susceptibility of LDL, catalase activity and NO levels were greatly enhanced. Finally, it increased the synthesis and release of cytokine (IL-1beta and TNF alpha). Treatment of diabetic rats with AG and omega 3FAs markedly reduced the above mentioned parameters. Combined form therapy has a better effect regarding oxidative cell markers, specifically NO level. Finally, omega 3FAs coadministration with AG nearly restored the atrophy of islets of Langerhan's and the peripheral lymphocytic infiltration compared to diabetic and AG treated groups. In conclusion, there is a direct correlation between glycation, oxidative stress and cytokine production with increased propensity of microvascular disorder in STZ diabetic rats. omega 3FA administration with AGE receptor blocker may represent a possible avenue of research for therapeutics directed for alleviating the complication associated with diabetes.